Allosteric Optical Control of a Class B G-Protein-Coupled Receptor

Johannes Broichhagen, Natalie R. Johnston, Yorrick Von Ohlen, Helena Meyer-Berg, Ben J. Jones, Stephen R. Bloom, Guy A. Rutter, Dirk Trauner, David J. Hodson

Research output: Contribution to journalArticlepeer-review

Abstract

Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G-protein-coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light-activated positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca2+, cAMP, and insulin responses to glucagon-like peptide-1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small-molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP-1R.

Original languageEnglish (US)
Pages (from-to)5865-5868
Number of pages4
JournalAngewandte Chemie - International Edition
Volume55
Issue number19
DOIs
StatePublished - May 4 2016

Keywords

  • GLP-1 receptor
  • allosteric regulation
  • beta cells
  • photopharmacology
  • type 2 diabetes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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